Brown Adipose Tissue Research Articles

Subacute Effects of Moderate-Intensity Aerobic Exercise in the Fasted State on Cell Metabolism and Signaling in Sedentary Rats.

Background: Physical inactivity induces insulin resistance (IR) and metabolic imbalances before any significant changes in adiposity. Recent studies suggest that the beneficial effects of exercise can be potentiated if performed while fasting. This work aimed to compare the subacute effects of fed- and fasted-state single-bout exercise on biochemical parameters and cellular signaling in the metabolism. Methods: The animals were allocated into fed rest (FER), fasting rest (FAR), fed exercise (FEE), and fasting exercise (FAE) groups. The exercise protocol was a 30 min treadmill session at 60% of V˙O2max. The fasting groups fasted for 8 h before exercise and were killed after 12 h post-exercise. Results: Soleus glycogen concentration increased only in the fasting groups, whereas the triglyceride (TGL) content increased in brown adipose tissue (BAT) and liver in the FAE. The FAE showed decreased plasma total cholesterol concentration compared withthe FAR group. Immunocontent of HSP70, SIRT1, UCP-1, and PGC1-α did not change in any tissue investigated. Conclusions: Our results indicate that physical exercise while fasting can have beneficial metabolic effects on sedentary animals. Remarkably, in the FAE group, there was a reduction in total plasma cholesterol and an increase in the capacity of BAT to metabolize and store nutrients in the form of TGLs.

Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics simulation studies

The prevalence of obesity is rapidly increasing worldwide. Brown adipose tissue activates uncoupling protein 1 (UCP1) to generate heat through bypassing ATP synthesis, offering a potential target for obesity treatment. Targeting UCP1 activation to induce thermogenesis through small molecules presents a promising approach for obesity management. In this study, molecular docking of UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference ligand (PDB ID: 8J1N, docking score: −5.343 kcal/mol), identified seven top-scoring compounds: naringin (-7.284 kcal/mol), quercetin (-6.661 kcal/mol), salsalate (-6.017 kcal/mol), rhein (-5.798 kcal/mol), mirabegron (-5.535 kcal/mol), curcumin (-5.479 kcal/mol), and formoterol (-5.451 kcal/mol). Prime MM-GBSA calculation of the top-scored molecule (i.e., naringin) in the docking study showed ΔGBind of −70.48 kcal/mol. Key interactions of these top 7 activators with UCP1 binding pocket residues Trp280, Arg276, Glu190, Arg83, and Arg91 were observed. Molecular dynamics simulations performed for 100 ns confirmed complex stability, with RMSD values below 6 Å. Additionally, most activators showed favorable intestinal absorption (>90 %) and lipophilicity (LogP 2–4), with pKa values supporting their pharmacological potential as UCP1-targeting therapeutics for obesity. These findings provide a foundation for designing potent UCP1 activators by integrating docking scores, interaction profiles, statistical profiles from MD simulations, and physicochemical assessments to develop effective anti-obesity therapies.

Brown adipose tissue activation in paediatric and adolescent oncological (Hodgkin lymphoma or sarcoma) cases visualised on FDG PET/CT

Brown adipose tissue activation in paediatric and adolescent oncological (Hodgkin lymphoma or sarcoma) cases visualised on FDG PET/CT

SOX4 facilitates brown fat development and maintenance through EBF2-mediated thermogenic gene program in mice.

Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.

Sympathetic Innervation of Interscapular Brown Adipose Tissue Is Not a Predominant Mediator of Oxytocin-Induced Brown Adipose Tissue Thermogenesis in Female High Fat Diet-Fed Rats.

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (TIBAT) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate TIBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated TIBAT similarly between sham rats and denervated rats (p = NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 μg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N = 7-8/group). Chronic 4V OT reduced body weight gain (sham: -18.0 ± 4.9 g; denervation: -15.9 ± 3.7 g) and adiposity (sham: -13.9 ± 3.7 g; denervation: -13.6 ± 2.4 g) relative to vehicle treatment (p < 0.05) and these effects were similar between groups (p = NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 (p < 0.05) and 3 (p < 0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice (p < 0.05 vs. vehicle). Together, these findings suggest that (1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and (2) the effects of OT to reduce weight gain and adiposity translate to other female mouse models of diet-induced obesity (DIO).

Effects of the Fungicide Prothioconazole on Lipid Metabolism in Mice: Whitening Alterations of Brown Adipose Tissue.

With considerable concerns about the associations between metabolic disorders and agricultural biocides, there are scattered data suggesting that the triazole fungicide prothioconazole (PTC) at lower doses than the no observed adverse effect level of 5000 μg/kg/d possibly has the potential to disrupt glycolipid metabolism in mammals. Here, we investigated the effects of 50, 500, and 5000 μg/kg/d of PTC on glycolipid metabolism in mice following 8 weeks of administration via drinking water, with specific attention on brown adipose tissue (BAT) and white adipose tissue (WAT) in addition to the liver. We found that along with the increased serum triglyceride level in the 5000 μg/kg/d group, small fatty vacuoles occurred in livers in all treatment groups, indicating lipid accumulation. No change in WAT was observed, but PTC caused BAT whitening, characterized by adipocyte hypertrophy, more unilocular adipocytes with enlarged lipid droplets, reduced UCP1 levels, and down-regulated Doi2 expression, and even the dose of 50 μg/kg/d was effective. Transcriptomic analysis revealed immune inhibition and circadian rhythm disturbance in BAT from the 5000 μg/kg/d group, which are in agreement with BAT whitening and inactivation. On employing the C3H10T1/2 cells in vitro, we found that PTC treatment concentration-dependently promoted lipid accumulation in brown adipocytes, along with altered expression of thermogenesis-related and circadian genes. Taken together, our study shows that low doses of PTC caused BAT whitening, calling for much attention to the new target by pollutants.

Impacts of time-restricted feeding on middle-aged and old mice with obesity.

Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.

Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.

Gut microbiota is involved in leptin-induced thermoregulation in Mongolian gerbil (Meriones unguiculatus).

Leptin is a hormone that secreted by adipocytes and may promote energy expenditure by increasing thermogenesis. Our previous studies have shown that thermo-transient receptor potentials (thermo-TRPs) and gut microbiota are associated with thermoregulation in Mongolian gerbils, which are characterized by relative high serum leptin concentrations. Here, we test whether leptin can stimulate non-shivering thermogenesis (NST) in Mongolian gerbils, and whether thermo-TRPs and gut microbiota are involved in leptin-induced thermogenesis. First, gerbils were given acute leptin treatment (ALT) with different doses. Results showed that ALT significantly increased the body temperature of gerbils and change the composition of gut microbiota. Moreover, ALT groups showed a trend towards increased expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). Then, we investigated the effect of chronic leptin treatment (CLT) on gerbils. Surprisingly, CLT did not affect gerbils' food intake and body weight, but it significantly increased the body temperature at the end. Besides, CLT did not affect the expression of thermogenic markers in BAT, white adipose tissue (WAT) and skeletal muscle. However, CLT increased the expression of leptin receptors and TRPV2 in the small intestine and affected the composition of gut microbiota. Together, our data suggest leptin may increase body temperature by regulating gut microbiota. In conclusion, the Mongolian gerbils with serum hyperleptin is beneficial for adapting the cold living environments, and TRPV2 and gut microbiota are involved.

Cold Exposure Therapy Sensitizes Nanodrug-Mediated Radioimmunotherapy of Breast Cancer.

Cold exposure (CE) therapy can quickly induce tumor starvation by brown adipose tissue (BAT) thermogenesis. Exploring the combined antitumor mechanism of CE and traditional therapies (such as radiotherapy (RT)) is exciting and promising. In this study, we investigated the effect of CE in combination with nitric oxide (NO) gas therapy on sensitizing tumors to RT and promoting tumor radio-immunotherapy. We first constructed a liposome (SL) loaded with the NO prodrug S-nitroso-N-acetylpenicillamine (SNAP). When SL is injected, the glutathione (GSH) within the tumor region promotes the release of NO from SNAP. Subsequently, the superoxide anion produced by RT reacts with NO to generate peroxynitrite (ONOO-), which has strong oxidative properties and induces cell death. Meanwhile, the mice were exposed to a CE environment of 4 °C. CE-mediated BAT thermogenesis induced tumor starvation, which led to a decrease in ATP and GSH content within the tumor as well as an improvement in the hypoxic microenvironment and a decrease in myeloid-derived suppressor cells. All of the above have promoted the effectiveness of RT and activated the systemic antitumor immunity. In the bilateral tumor experiment, treatment of the primary tumor inhibited the growth of the distant tumor and promoted the infiltration of CD8+ T cells into the tumor. These findings reveal that the synergy of CE, NO gas therapy, and RT could confer high effective anticancer effects, providing possibilities in personalized cancer treatment.

Quantification of nutrient fluxes during acute exercise in mice.

Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use invivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.

FDG Uptake in Brown Adipose Tissue Activated by a Long-Acting β2-Adrenergic Receptor Agonist Inhaler Prescribed for Bronchial Asthma.

We herein report a case of an elderly woman in whom brown adipose tissue (BAT) was visible on 18 F-FDG PET imaging performed in the summer. In this patient, none of the well-known factors that induce BAT activation in adults, including cold exposure, catecholamine-producing tumors, or β3-adrenergic receptor agonists administration, were present. Daily inhalation of a long-acting β2-adrenergic agonist for treatment of her bronchial asthma was considered the cause of her BAT visualization. This case suggests the need to consider β2-adrenergic receptor agonists as a cause of BAT visualization.

Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity.

Bimagrumab is a human monoclonal antibody that prevents activin type II receptors (ActRII) from functioning. This antibody has a higher affinity for muscle activin-2 receptors than natural ligands such as activin and myostatin, which act as negative muscle growth regulators. Blocking the activin receptor with bimagrumab could be a new pharmaceutical approach for managing patients with obesity and type 2 diabetes mellitus (T2DM). Bimagrumab has anabolic effects on skeletal muscle mass by preventing myostatin binding and other negative muscle growth regulators. Preclinical animal models have also shown that ActRII blockade promotes actions beyond skeletal muscle, including effects on brown adipose tissue (BAT) differentiation and activity. In a phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of total body fat mass (FM), lean mass (LM) gain, and metabolic improvements over 48weeks in overweight or obese patients with type 2 diabetes. The trial involved [number of participants], and the results showed [specific findings]. Currently, Bimagrumab is being evaluated for its potential to treat muscle wasting, functional loss in hip fractures and sarcopenia, as well as obesity. However, it is essential to note that Bimagrumab also blocks the effects of other ActRII ligands, which play a role in the neurohormonal axes, pituitary, gonads, and adrenal glands. These observations suggest that bimagrumab might represent a new approach for treating patients with obesity and related metabolic disturbances.

Brown adipose tissue: a potential target for aging interventions and healthy longevity.

Brown Adipose Tissue (BAT) is a type of fat tissue that can generate heat and plays an important role in regulating body temperature and energy metabolism. Enhancing BAT activity through medication, exercise and other means has become a potential effective method for treating metabolic disorders. Recently, there has been increasing evidence suggesting a link between BAT and aging. As humans age, the volume and activity of BAT decrease, which may contribute to the development of age-related diseases. Multiple organelles signaling pathways have been reported to be involved in the aging process associated with BAT. Therefore, we aimed to review the evidence related to the association between aging process and BAT decreasing, analyze the potential of BAT as a predictive marker for age-related diseases, and explore potential therapeutic strategies targeting BAT for aging interventions and healthy longevity.

Autophagy Alterations in White and Brown Adipose Tissues of Mice Exercised under Different Training Protocols.

Autophagy is a conserved catabolic process that promotes cellular homeostasis and health. Although exercise is a well-established inducer of this pathway, little is known about the effects of different types of training protocols on the autophagy levels of tissues that are tightly linked to age-related metabolic syndromes (like brown adipose tissue) but are not easily accessible in humans. Here, we take advantage of animal models to assess the effects of short- and long-term resistance and endurance training in both white and brown adipose tissue, reporting distinct alterations on autophagy proteins microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B, or LC3B) and sequestosome-1 (SQSTM1/p62). Additionally, we also analyzed the repercussions of these interventions in fat tissues of mice lacking autophagy-related protein 4 homolog B (ATG4B), further assessing the impact of exercise in these dynamic, regulatory organs when autophagy is limited. In wild-type mice, both short-term endurance and resistance training protocols increased the levels of autophagy markers in white adipose tissue before this similarity diverges during long training, while autophagy regulation appears to be far more complex in brown adipose tissue. Meanwhile, in ATG4B-deficient mice, only resistance training could slightly increase the presence of lipidated LC3B, while p62 levels increased in white adipose tissue after short-term training but decreased in brown adipose tissue after long-term training. Altogether, our study suggests an intricated regulation of exercise-induced autophagy in adipose tissues that is dependent on the training protocol and the autophagy competence of the organism.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Comparing total-body metabolic PET imaging signatures of lung cancer cachexia to other wasting conditions

Cancer cachexia (CC) is a debilitating wasting condition. While anorexia and muscle wasting are features of cachexia, CC is a distinct and poorly understood metabolic syndrome1. We harnessed preclinical models of lung cancer to study how glucose uptake changes during CC and performed comparative analyses with anorexia and muscle wasting. Lung K-rasG12D/+;Lkb1-/-(KL) mice suffering CC were imaged using [18F]fluorodeoxyglucose (FDG) PET at 15-19% weight loss alongside K-ras wild-type (WT) non-tumour bearing controls. Mice were injected with 12-18MBq of FDG, imaging 80-100 minutes post injection with the Mediso nanoScan® PET/MRI 1T. In non-tumour bearing male animals, we modelled anorexia, muscle wasting, and circulation of cachexia factor GDF15 as follows, respectively: fasted overnight for 20 hr, treated with dexamethasone 21-phosphate (dexa) (2mg/kg, i.p. daily, 21 days) and single injection of recombinant human GDF15 hormone (0.1 mg/kg s.c.). FDG ex vivo biodistribution showed increased uptake in myocardium (p&lt;0.05), brain and liver (both p&lt;0.01) of KL cachexic animals with no significant change in FDG blood pool. Like cachexic KL animals, FDG uptake in fasted animals increased in brain (p&lt;0.0001), perhaps due to increased FDG blood pool. FDG uptake in skeletal muscles and brown adipose tissue decreased (both p&lt;0.05) in fasted state suggesting lower muscle activity and decreased thermogenesis respectively. Dexa-induced muscle atrophy also resulted in decreased FDG uptake in gastrocnemius/soleus muscles (SUVmean 0.63 vehicle vs. 0.45 dexa, p&lt;0.05) but no changes in skeletal muscle FDG uptake were noted in cachexic animals. In contrast to KL animals, GDF15 injection resulted in decreased FDG uptake in myocardium (p&lt;0.05). Overall, the cachexic FDG signature showed differences to other wasting conditions in this mouse model, suggesting different underlying mechanisms. Total-body PET can reveal diverse metabolic wasting states. We aim to elucidate mechanisms of metabolic changes in cachexia to allow metabolic subtyping and personalised treatment options. Please click on the 'PDF' for the full abstract!

The effect of pre-partum shearing of Corriedale ewes on placental and lamb development and neonatal behaviour.

To evaluate the effects of early and late pre-partum shearing of Corriedale ewes carrying single fetuses on placental and lamb development and neonatal lamb behaviour. At 70 days of gestation, 37 multiparous Corriedale ewes with known gestation dates were randomly allocated into three groups: S70 (n = 12) and S110 (n = 12), shorn at Day 70 and 110 of gestation, and US (n = 13), that were not shorn pre-partum. Gestation length, lambing duration, placental expulsion time, placental weight, number and weight of cotyledons, and placental efficiency (lamb weight/placental weight) were determined. At birth, body temperature, weight, morphometric measurements, ponderal index (lamb weight/lamb crown-rump length) and behaviour were recorded, with weight remeasured 72 hours later. Four male lambs per group were slaughtered immediately after parturition, and organ weight and perirenal brown fat weight and energy content recorded. Pre-partum shearing, regardless of timing, increased total dried placental weight per ewe. Pre-partum shearing at Day 70 of gestation increased the number and mean weight of the > 2 to ≤ 3-cm cotyledons, while pre-partum shearing at Day 110 of gestation increased only the weight of these cotyledons. At birth and at 72 hours, lambs from ewes shorn either at 70 days of gestation (birth: 5.5 (95% CI = 4.6-6.4) kg, p = 0.001; 72 hours: 6.4 (95% CI = 6.1-6.8) kg, p = 0.002) or at 110 days of gestation (birth: 5.4 (95% CI = 4.4-6.4) kg, p = 0.001; 72 hours: 6.5 (95% CI = 5.9-7.1) kg, p = 0.001) were heavier than lambs from unshorn ewes (birth: 4.0 (95% CI = 3.3-4.8) kg; 72 hours: 4.8 (95% CI = 3.5-6.1) kg). Lambs born to S70 and S110 ewes suckled sooner (31.5 (95% CI = 14.5-48.5) minutes, p = 0.001; and 39.3 (95% CI = 23.7-55.0) minutes, p = 0.001 respectively), than lambs born to the US group (70.3 (95% CI = 38.6-102.1) minutes). There was no evidence for an effect of pre-partum shearing on gestation length, parturition length, time of placental expulsion, placental efficiency, weight and energy of perirenal brown fat, and lamb temperature at birth. Shearing ewes pre-partum may lead to placental changes affecting lamb development and behaviour and associated with higher survival. The findings suggest pre-partum shearing may improve lamb survival, farm profitability and sustainability.

8353 Impact of a plant-based protein diet on bone health and body composition in Sprague Dawley rats

Abstract Disclosure: M.M. Gomes: None. I.M. de Araújo: None. S.V. Rodriguez: None. F.R. Jorge: None. F.J. de Paula: None. Introduction:Vegetarian and vegan diets are associated with some health benefits; this has contributed to their growing popularity. Although studies remain limited, there is evidence that these patients may be at greater risk of reduced bone mineral density (BMD) and increased fracture risk. The general objective of this study was to analyze the impact of a high-protein, plant-based diet on bone tissue and body composition in male Sprague Dawley rats. Methodology: The study was approved by the Animal Ethics Committee. This study was done with 10 rats in the control group (CG), which received a standard AIN-93M diet; 11 in the normoprotein vegetarian group (NVG), with a normoprotein AIN-93 diet modified with pea protein and methionine; and 11 in the high-protein vegetarian group (HVG), with a modified AIN-93 diet with 40% pea protein and methionine. The dietary intervention lasted 8 weeks. The weight of the animals was measured weekly. Basal blood glucose levels were measured at baseline. At the end of the study, 6 rats from the CG, 6 rats from the NVG, and 5 rats from the HVG were subjected to a glucose tolerance test (GTT). The dual-energy X-ray absorptiometry (DXA) technique was applied in the baseline and final periods of the experiment to evaluate body composition, bone mineral content (BMC) and BMD. After sacrifice, bone strength was measured via a three-point flexion mechanical test on the tibia; brown adipose, epididymal, and retroperitoneal tissues, as well as the liver, were weighed on an analytical balance. Blood was used to measure circulatory levels of insulin, CTX, and P1NP (n=6/group). Results: Basal weight was similar between the groups, but the final weight was lower in the HVG as compared to the CG. In the DXA evaluation, the final lean mass was not different between the groups. On the other hand, total fat mass was lower in the HVG than in the CG and the NVG and the fat percentage was lower in the HVG than in the CG. The weight of epididymal adipose tissue was lower in the HVG than in the NVG, but retroperitoneal and brown adipose tissues were lower in HVG than CG. Liver weight was similar between groups. BMD was similar between groups; however, BMC was lower in the HVG than in the CG and the NVG. Bone strength was similar between groups. There was no difference in glycemia at baseline or during GTT at the eighth week. Serum levels of insulin, CTX, and P1NP were similar between groups. Discussion and Conclusion: A normoprotein vegetarian diet that includes all essential amino acids appears to have no negative impact on body composition or BMD in rats. On the other hand, a high-protein diet with plant protein appears to have a negative impact on bone mineral content, in addition to reducing the amount of body fat and weight. This finding expands on previous results by showing that high-protein diets have a negative impact on bone even when the protein is of plant origin. Presentation: 6/1/2024

8515 Role of Insulin Receptor in Trpv1-positive Adipocyte Progenitor Cellsin Adipocyte Differentiation and Metabolic Function

Abstract Disclosure: C. Sahin: None. H. Camara: None. F. Shamsi: None. M. Lynes: None. Y. Tseng: None. Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, is an important endocrine organ in the regulation of energy balance. Stimulating BAT activation and beiging of white adipose tissue (WAT) are new strategies to combat metabolic diseases, such as obesity and diabetes. Traditionally, thermogenic adipocytes are known to originate from mesenchymal Pdgfrα-expressing adipocyte progenitor cells (APCs). A previous study conducted by our lab identified vascular smooth muscle cells as a novel cellular origin of APCs. These cells are characterized by the expression of transient receptor potential cation channel subfamily V member 1 (Trpv1+). With cold exposure, the Trpv1+ APC-derived adipocytes are increased in BAT and WAT and differentiated into highly thermogenic adipocytes. These findings indicate that the Trpv1+-APCs may play an important role in the development of brown and beige adipocytes in response to cold. This study was designed to explore the function of the Trpv1+ APC-derived adipocytes in thermogenic adipocyte differentiation and metabolic regulation. We generated a mouse model in which insulin receptor (IR), a well-known player in adipocyte differentiation, was deleted in the Trpv1+ APCs to impair their adipogenic potential. Trpv1-Cre::mTmG::IRflox transgenic and IRwt control mice were housed at cold temperature (5°C) for 7 days. Because the lineage tracing mTmG system was included, we were able to trace the fate of Trpv1+ APCs in the presence or absence of IR. We first examined the adipogenic capacity of the IR-deficient Trpv1+ cells in BAT and WAT tissues using whole-mounted adipose tissue imaging. In control mice, approximately 30% of all mature adipocytes were derived from Trpv1+ APCs in adipose tissue in response to cold. With ablation of IR in Trpv1+ APCs, this contribution was significantly reduced in BAT (by 11.7 % in females; 6.1% in males), inguinal WAT (by 16.8% in females; 19.3% males), and perigonadal WAT (by 11.4% in females; 14.8% in males) in transgenic mice compared to control mice. These results showed that IR-deficiency in the Trpv1-expressing cells impaired their adipogenesis in both male and female mice. In contrast, thermogenic genes (e.g., Ucp1, Pparγc1a, Cox7a1) were not significantly altered in BAT and inguinal WAT of the IR-deficient Trpv1+ APCs mice. Despite the changes in the adipocyte populations, we observed that deletion of IR in Trpv1+ APCs has no impact on body weight, food intake, fat mass, glucose tolerance, and insulin sensitivity relative to control mice. Taken together, blocking the contribution of Trpv1+ APCs to the mature adipocyte population results in no metabolic changes in mice, suggesting that the other APCs, such as PdgfRα+ APCs, may potentially compensate for impaired adipogenesis in different adipose tissues. Presentation: 6/1/2024